TELOMERASE: A NOVEL TARGET OF ANTITUMOR AGENTS

Telomerase activity was found to be high in various human cancers, but absent in most normal tissues. Its expression pattern made it a novel target for antitumor agents. Several strategies against telomerase were presented in this review. Targeting the telomerase RNA component by oligonucleotide/ribozyme was considered to be one of the most hopeful approaches. Some progresses were made in this area, such as the use of PANs and 2–5A antisense compounds. The relationships among telomerase activity and cell differentiation, signal transduction, oncogene, tumor suppressor gene as well as cell cycle modulation also provided a series of valuable ideas in designing anti-telomerase drugs for cancer therapy. In conclusion, although there is still a long way in understanding the mechanism and regulation of telomerase, the advance of studies on telomerase has allowed the development of numerous strategies for the treatment of cancer.

EFFECTS OF VARIOUS VASOACTIVE AGENTS ON TUMOR BLOOD FLOW IN RAT

Effects of angiotensin Ⅱ and other six vasoactive agents on tissue blood flow of Yoahida rat ascites hepatoma AH109A and normal liver were measured by the hydrogen clearance method. The mean blood flow in the tumor peripheral part under normal tension was 11. 9±8. 2ml/ min/100g tissue and was not influenced by tumor size. Tumor blood flow was more significantly increased in infusion angiotensin Ⅱthan 0.5mg/ ml methoxamine, however, normal liver blood flow of tumor-bearing rats was unchanged in contrast to an Increase seen in the tumor. A pronounced reduction of tumor blood flow was found after administration of epinephrine, norepinephrin and ethylphenylephrine. In addition, metaraminol and phenyleprine as well as 1. 0 and 2. 5mg/ ml methoxamine were not found to significantly change blood flow of the tumor.

Gastrointestinal tumors and infectious agents:A wide field to explore

Infection is currently one of the main contributors to carcinogenesis.In fact,the International Agency for Research on Cancer has categorized eleven biological agents as group I carcinogens.It is estimated that around 16%of the 12.7 million new cancers diagnosed in 2008 were attributable to infectious agents.Although underdeveloped regions carry the highest incidence rates,about 7.4%of infectionrelated cancer cases occur in developed areas.Physicians are increasingly aware of the potential carcinogenic role of common virus like the Human Papilloma virus in cervical cancer,or the hepatitis B and C viruses in hepatocarcinoma.However,the carcinogenic role of several other infectious agents is less recognized.Given that gastrointestinal malignancies carry an overall poor prognosis,a better understanding of the carcinogenic mechanisms triggered by infectious agents is key to decrease the rate of cancer related deaths.Preventive measures directed to such infections would ideally impact survival.In this paper we review the main pathogenic mechanisms related to the development of gastrointestinal malignancies induced by infectious microorganisms and other pathogens which are currently under investigation.

Imaging tumor hypoxia:Blood-borne delivery of imaging agents is fundamentally different in hypoxia subtypes

Dedicated to the memory of Professor Briton Chance on the ccasion of his 100th birthday(July24 th,2013),and remembering mary erciting discussions on the orygenation of breast cancer,ontumor hyporia in general and imaging of the orygenation status of malignant tumors.Hypoxic tissue subvolumes are a hallmark feat ure of solid malignant tumors,relevant for cancertherapy and patient outcome because they increase both the intrinsic aggressiveness of tumor cells and their resist ance to several commonly used anticancer strategies.Pathogenetic mech-anisms leading to hypoxia are diverse,may coexist within the same tumor and are commonlygrouped according to the duration of their ffects.Chronic hypoxia is mainly caused by difusionlimitations resulting from enlarged intercapilary distances and adverse difusion geometriesand--to a lsser extent--by hypoxemia,compromised perfusion or long-lasting microregionalfow stops.Conversely,acute hypoxia preferentilly results from transient disruptions in per.fusion.While each of these features of the tumor microenvironment can contribute to a criticalreduction of oxy gen availability,the delivery of imaging agents(as well as nutrients and anti-cancer agents)may be compromised or remain unaffected,Thus,a critial appraisal of the ffectsof the various mechanisms leading to hypoxia with regard to the blood-bome delivery of imagingagents is necessary to judge their ability to correctly represent the hypoxic phenotype of solidmalignancies.

Clinical application of several tumor imaging agents

Neoplasms is one of the main diseases for harming health. It is difficult to prevent the neoplasms because the factors of bringing out them are complex. To raise survival rate the early diagnosis of tumors is very important. Radionuclide imaging is useful to detect recurrent or residual disease and to identify benign or malignant tumor. Several tumor imaging agents as following have clinical significance in diagnosing tumors.

Survey of Radiosensitizing Agents (Synthesized Chemicals and Gene Therapeutic Agents) Since 2000

Radiotherapy has played an important role in treatment of tumor patientssince it appeared about 80 years ago, and has been an indispensable part of the management of about50% of tumors (especially 60% - 70% of malignant tumors). Currently, radiotherapy is used in simpleand palliative therapy, adjuvant therapy after or before surgery, simultaneous radio-chemotherapy,combined BRM (biological response modifier) therapy, ets. Radiosensitizing agents enhance theradiation effects on tumor cells so as to have better responses in radiotherapy. Tumor intrinsicradiosensitivity is affected by the hy-poxic level in solid tumor, the ability of the cells torepair the radiation-induced DNA damage, the number of cells which have a clonogenic capability toreestablish uncontrolled cell growth, the amount of dividing cells, and the distribution of cellsthroughout the cell cycle. Consequently , it is necessary and useful to add one or moreradiosensitizing agents in radiotherapy to increase the radio-sensitivity of tumor cells.

Survey on Natural Radiosensitizing Agents Since 2000

Actually, radiation alone is not enough to kill tumor cells efficientlybecause of the radioresistance of tumor cells. It is well known that tumors from the samehistolog-ical origin and of the same development stage are extremely heterogeneous in theirsensitivity to radiotherapy. One of the most resistant factors to radiation is that tumor cells arecommonly hypoxic. The study on radiosensitizing agents is one of the most interesting issues intumor radiotherapeutics. These radiosensitizing agents can be classified into three main categories:natural products, synthesized chemicals and gene therapeutic agents according to their origins andtherapeutic techniques. Many radiosensitizing agents have some side-effects when they are active;so, it is important and significant to do our best to find more radiosensitizing agents with higherefficiency and lower side-effects. On the other hand, the tumor cells are easy to become resistantto older radiosensitizing agents; hence, it is urgent to develop newer radiosensitizing agents forclinics. Natural products come from plants, animals and other living beings. When serving asradiosensitizing agents in tumor radiotherapy, they are more attractive and predominant than generaldrugs. The reasons include a great resource ( especially in China) , multifunctional regulation,higher effectiveness and safer clinical effects.

Non-thermal ablation of rabbit liver VX2 tumor by pulsed high intensity focused ultrasound with ultrasound contrast agent:Pathological characteristics

AIM： To investigate the pathological characteristics of non-thermal damage induced by pulsed high intensity focused ultrasound （PHIFU） combined with ultrasound contrast agent （UCA）, SonoVue （Bracco SpA, Milan, Italy） in rabbit liver VX2 tumor. METHODS： Liver VX2 tumor models were established in 20 rabbits, which were divided randomly into PHIFU combined with ultrasound contrast agent group （PHIFU ＋ UCA group） and sham group. In the PHIFU ＋ UCA group, 0.2 mL of SonoVue was injected intravenously into the tumor, followed by ultrasound exposure of Isp 5900 W/cm^2. The rabbits were sacrificed one day after ultrasound exposure. Specimens of the exposed tumor tissues were obtained and observed pathologically under light microscope and transmission electron microscope. The remaining tumor tissues were sent for 2,3,5-Triphenyltetrazolium chloride （TTC） staining. RESULTS： Before Trc staining, tumor tissues in both the sham and the PHIFU ＋ UCA groups resembled gray fish meat, After TIC staining, the tumor tissues were uniformly stained red, with a clear boundary between tumor tissue and normal tissue, Histological examination showed signs of tumor cell injury in PHIFU ＋ UCA group, with cytoplasmic vacuoles of various sizes, chromatin margination and karyopyknosis. Electron microscopic examination revealed tumor cell volume reduction, karyopyknosis, chromatin margination, intercellular space widening, the presence of high electro＇n-density apoptotic bodies and vacuoles in cytoplasm. CONCLUSION： The non-thermal effects of PHIFU combined with UCA can be used to ablate rabbit liver VX2 tumors.

PERCUTANEOUS INJECTING ANTINEOPLASTIC AGENT INTO TRANSPLANTED TUMORS OF MICE BY CT－GUIDED

Antineoplastic agent and contrast medium were injected into transplanted tumors of mice under guidance with CT, site and range of the intratumoural drug were shown on CT image immediately. It was value of multipoint injections, concentration of 0.1 mg/0.l ml MMC every point, 1 cm interval of injection. After the injections, the tumor size of mice reduced and at last disappeared (ratio of inhibited tumor 59.32% in 0.05 mg MMC group, 43.86% in 0.1 mg MMC group).The pathologic examination showed coagulatic necrosis of the tumor tissues. The higher concentration of antineoplastic agent (0.2 mg MMC) could make the tumors enlarged (ratio of inhibited tumor -15.3%). The tissues and vessels around the tumors were not injured, if MMC overflow out off the tumor.

Safety and efficacy of anti-tumor necrosis factors α in patients with psoriasis and chronic hepatitis C

Up to date,in literature,it is still debated the role of anti-tumor necrosis factors(TNF)-α treatments in hepatitis C virus(HCV) patients.TNF-α performs a lot of functions,it is an important pro-inflammatory cytokine and it is involved in the host's immunity.Since TNF-α is implicated in the apoptotic signaling pathway of hepatocytes infected by HCV,anti TNF-α therapy may increase the risk of viral replication or their reactivation.However the treatment of anti TNF-α could have a healthful role because TNF-α appears to be engaged in the pathogenesis of liver fibrosis,inducing apoptotic pathways.We describe the case of a patient with plaquetype psoriasis and concomitant chronic HCV,who was treated successfully with anti-TNF agents simultaneously to cyclosporine without sign of reactivation of HCV and increase of liver enzymes.Our personal experience shows that anti-TNF-α agents are not only effective but also safe.Furthermore the combination therapy of cyclosporine and anti-TNF-α appears to be well-tolerated and able to reduce the amount of liver enzymes as well as HCV-viral-load.However systematic,large-scale studies with long follow-ups will be needed to confirm our results,in association with close liver function monitoring.

Topical biological agents targeting cytokines for the treatment of dry eye disease

Because inflammation plays a key role in the pathogenesis of dry eye disease and Sjogren's syndrome, topical anti-inflammatory agents such as corticosteroids and cyclosporine A have been used to treat inflammation of the ocular surface and lacrimal gland. Systemic biological agents that target specific immune molecules or cells such as tumor necrosis factor(TNF)-α, interferone-α, interleukin(IL)-1, IL-6, or B cells have been used in an attempt to treat Sjogren's syndrome. However, the efficacy of systemic biological agents, other than B-cell targeting agents, has not yet been confirmed in Sjogren's syndrome. Several studies have recently evaluated the efficacy of topical administration of biological agents targeting cytokines in the treatment of dry eye disease. Topical blockade of IL-1 by using IL-1 receptor antagonist could ameliorate clinical signs and inflammation of experimental dry eye. Using a mouse model of desiccating stress-induced dry eye, we have demonstrated that topical application of a TNF-α blocking agent, infliximab, could improve tear production and ocular surface irregularity, decrease inflammatory cytokines and Th-1 CD4+ cells on the ocular surface, and increase gobletcell density in the conjunctiva. Although controversy still remains, the use of topical biological agents targeting inflammatory cytokines may be a promising therapy for human dry eye disease.

Labeling and stability study On^（99m）Tc－tissue plasminogen activator as thrombus and tumor imaging agent

ＬａｂｅｌｉｎｇａｎｄｓｔａｂｉｌｉｔｙｓｔｕｄｙＯｎ￣（９９ｍ）Ｔｃ－ｔｉｓｓｕｅｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒａｓｔｈｒｏｍｂｕｓａｎｄｔｕｍｏｒｉｍａｇｉｎｇａｇｅｎｔＬｉＷｅｉ－Ｙｉ（李卫一），ＣａｏＧｕｏ－Ｘｉａｎ（曹国宪），Ｙｕ...

Arterial-phase contrast-enhanced ultrasonography for evaluating anti-angiogenesis treatment: A pilot study

AIM:To verify whether arterial-phase contrast-enhanced ultrasonography(CEUS) of tumor parenchymal tissue is useful for evaluation of anti-angiogenesis agents.METHODS:Rabbits with liver tumor were subjected to CEUS,and images of the nodular maximal diameter in vascular phase were recorded.Image analysis was performed to plot the time intensity curve(TIC) at the tumor parenchyma,which set the diameter of the region of interest of intensity measurement.The TIC was calculated to obtain the time to peak intensity(TPI) and the magnitude of PI.Rabbits were randomly assigned to a treatment group with sorafenib and a control group.Two weeks later,the same ultrasound examination was repeated followed by pathological testing to assess the effect of sorafenib on the liver tumor.RESULTS:In four rabbits in the treatment group,the rate of change of tumor size was decreased comparedwith that of the control(the rate 2.3 vs 7.9,P = 0.02).The TPI of the treatment group elongated significantly(the rate 3.1 vs 1.1,P = 0.07 for SonoVue,2.0 vs 0.88,P = 0.09 for Sonazoid).The magnitude of PI showed no significant changes.In pathological examination,capillary diameters in the treatment group were significantly smaller than those in the control group(26.4 vs 42.8 μm,P = 0.013).CONCLUSION:Analysis of the TIC in the arterial phase of tumor tissue could evaluate the efficacy of antiangiogenesis drug treatment in liver tumor.

Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations

Pancreatic neuroendocrine tumors(PNETs)are known to be the second most common epithelial malignancy of the pancreas.PNETs can be listed among the slowest growing as well as the fastest growing human cancers.The prevalence of PNETs is deceptively low;however,its incidence has significantly increased over the past decades.According to the American Cancer Society’s estimate,about 4032(>7%of all pancreatic malignancies)individuals will be diagnosed with PNETs in 2020.PNETs often cause severe morbidity due to excessive secretion of hormones(such as serotonin)and/or overall tumor mass.Patients can live for many years(except for those patients with poorly differentiated G3 neuroendocrine tumors);thus,the prevalence of the tumors that is the number of patients actually dealing with the disease at any given time is fairly high because the survival is much longer than pancreatic ductal adenocarcinoma.Due to significant heterogeneity,the management of PNETs is very complex and remains an unmet clinical challenge.In terms of research studies,modest improvements have been made over the past decades in the identification of potential oncogenic drivers in order to enhance the quality of life and increase survival for this growing population of patients.Unfortunately,the majority of systematic therapies approved for the management of advanced stage PNETs lack objective response or at most result in modest benefits in survival.In this review,we aim to discuss the broad challenges associated with the management and the study of PNETs.

Experimental study on antitumor effect of arsenic trioxide in combination with cisplatin or doxorubicin on hepatocellular carcinoma

INTRODUCTIONThe main component of a traditional Chinese drug 'Pishuang'. arsenic trioxide (As2O3), has obviously selective anti-tumor effect on human hepatocellular carcinoma (HCC)in both in vitro and in vivo studies[1-5]. Due to limited effectiveness when any anti-carcinogen is used alone and obviously increased toxicity when the dose is raised, there is no exception for As2O3. Furthermore, combined chemotherapy contributes to improve therapeutic effectiveness, disperse toxicity and surmount drug-resistance,in which the combination of traditional Chinese and modern medicine has more advantages and characteristics. As a result,we made an experimental study on anti-tumor effect of As2O3in combination with cisplantin (PDD) or doxorubicin (ADM)on HCC. to investigate the possibility of AS2O3 in combination with PDD or ADM and nature of interaction between them,and to provide experimental basis for clinical application.

Adeno-associated virus mediated endostatin gene therapy in combination with topoisomerase inhibitor effectively controls liver tumor in mouse model

AIM:rAAV mediated endostatin gene therapy has been examined as a new method for treating cancer.However, a sustained and high protein delivery is required to achieve the desired therapeutic effects.We evaluated the impact of topoisomerase inhibitors in rAAV delivered endostatin gene therapy in a liver tumor model. METHODS:rAAV containing endostatin expression cassettes were transduced into hepatoma cell lines.To test whether the topoisomerase inhibitor pretreatment increased the expression of endostatin,Western blotting and ELISA were performed.The biologic activity of endostatin was confirmed by endothelial cell proliferation and tube formation assays. The anti-tumor effects of the rAAV-endostatin vector combined with a topoisomerase inhibitor,etoposide,were evaluated in a mouse liver tumor model. RESULTS:Topoisomerase inhibitors,including camptothecin and etoposide,were found to increase the endostatin exPression level in vitro.The over-expressed endostatin, as a result of pretreatment with a topoisomerase inhibitor, was also biologically active.In animal experiments,the combined therapy of topoisomerase inhibitor,etoposide with the rAAV-endostatin vector had the best tumor- suppressive effect and tumor foci were barely observed in livers of the treated mice.Pretreatment with an etoposide increased the level of endostatin in the liver and serum of rAAV-endostatin treated mice.Finally,the mice treated With rAAV-endostatin in combination with etoposide showed the longest survival among the experimental models. CONCLUSION:rAAV delivered endostatin gene therapy in combination with a topoisomerase inhibitor pretreatment is an effective modality for anticancer gene therapy.

Synthesis and in vitro biological evaluation of nitric oxide-releasing derivatives of hydroxylcinnamic acids as anti-tumor agents

Novel furoxan-based nitric oxide-releasing derivatives 6a-p of hydroxylcinnamic acids were synthesized by coupling the carboxyl group of hydroxylcinnamic acids with furoxan through various alkylol amines.Compounds 6a,e-i and m-p displayed more potent anti-tumor activities superior to control 5-fluorouracil（5-FU） in most cancer cells tested.Furthermore,6f could selectively inhibit tumor cells,but not non-tumor cell proliferation.This inhibition was attributed to high levels of NO released in cancer cells and potentially synergistic effect of NO donor moieties and the bioactivity of hydroxylcinnamic acids.

Separate calculation of DW-MRI in assessing therapeutic effect in liver tumors in rats

AIM:To explore whether the antitumor effect of a vascular disrupting agent(VDA)would be enhanced by combining with an antiangiogenic agent,and whether such synergistic effects can be effectively evaluated with separate calculation of diffusion weighted magnetic resonance imaging(DW-MRI).METHODS:Thirty-seven rats with implanted liver tumors were randomized into the following three groups:(1)ZD6126,a kind of VDA;(2)ZDTHA,ZD6126 in combination with an antiangiogenic,thalidomide;and(3)control.Morphological DW-MRI were performed and quantified before,4 h and 2 d after treatment.The apparent diffusion coefficient(ADC)values were calculated separately for low b values(ADC low),high b values(ADC high)and all b values(ADC all).The tissue perfusion contribution,ADC perf,was calculated as ADC low-ADC high.Imaging findings were finally verified by histopathology.RESULTS:The combination therapy with ZDTHA significantly delayed tumor growth due to synergistic effects by inducing cumulative tumor necrosis.In addition to delaying tumor growth,ZDTHA caused tumor necrosis in an additive manner,which was verified by HE staining.Although both ADC high and ADC all in the ZD6126and ZDTHA groups were significantly higher compared to those in the control group on day 2,the entire tumor ADC high of ZDTHA was even higher than that of ZD6126,but the significant difference was not observed for ADCall between ZDTHA and ZD6126.This indicated that the perfusion insensitive ADC high values calculated from high b value images performed significantly better than ADC all for the monitoring of tumor necrosis on day 2.The perfusion sensitive ADC perf derived from ADC low by excluding high b value effects could better reflect the reduction of blood flow due to the vessel shutdown induced by ZD6126,compared to the ADC low at 4 h.The ADC perf could provide valuable perfusion information from DW-MRI data.CONCLUSION:The separate calculation of ADC is more useful than conventional averaged ADC in evaluating the efficacy of combination therapy with ZD6126and thalidomide for solid tumors.

Study on the correlation between tumor necrosis factor and nerve root pain

Objective To study the correlation between TNF and nerve root pa in ,and try to find ou t its significance.Methods45cases who had cervical syndr ome,lumbar di sc protrusion and lumbar spine stenosis were studied .TNF in blo od serum w as determined with subsequence saturation liquid phase competitiv e r adio-immunity,and the results we re further statistically processed.Results T NF value in 45cases was higher than normal value(P <0.01).T-check-ou t was made between pain d egree,we gained P <0.01.Conclusion There is not able correlation between TNF and nerve ro ot pain,which is benifit to guide cli nical diagnosis and treatment .

Synthesis and in vitro biological evaluation of farnesylthiosalicylic acid derivatives as anti-tumor carcinoma agents

Novel farnesylthiosalicylic acid （PTA） derivatives 5a-m with different substituted 1,3,4-thiadiazoles were synthesized. Compounds 5b, 5e, 5e and 5f displayed anti-tumor activities superior to FTA in most cancer cells tested. Furthermore, 5e induced tumor cell apoptosis, which was accompanied by lower Bcl-2 expression, but with higher Bax and caspase 3 expression activities in cancer cells.